Use of Common Psychiatric Medications and Risk and Prognosis of Amyotrophic Lateral Sclerosis

Importance Although several studies have shown an increased risk of subsequent amyotrophic lateral sclerosis (ALS) diagnosis for individuals with a history of psychiatric disorders, the evidence of an association between use of common psychiatric medications and ALS is scarce and inconclusive. Objective To examine whether there is an association of prescribed use of common psychiatric medications, namely anxiolytics, hypnotics and sedatives, and antidepressants, with the risk and disease progression of ALS. Design, Setting, and Participants This nationwide register-based case-control study was conducted in Sweden among all patients diagnosed with ALS from January 1, 2015, to July 1, 2023, according to the Swedish Motor Neuron Disease Quality Registry, who were age- and sex-matched with as many as 5 individuals with no ALS as well as their full siblings and spouses. Patients with ALS were followed up for a median (IQR) of 1.33 (0.64-2.37) years after diagnosis. Exposures At least 2 prescriptions of the studied psychiatric medications before ALS diagnosis. Main Outcomes and Measures The risk of ALS diagnosis associated with prediagnostic prescribed use of common psychiatric medications was estimated using conditional logistic regression models, comparing patients with ALS with population or relative control participants. Patients with ALS were followed up from diagnosis to assess the association of prediagnostic prescribed use of common psychiatric medications with disease progression. The association of mortality (or use of invasive ventilation) with the use of common psychiatric medications was estimated with a joint longitudinal-survival model accounting for the longitudinal changes of ALS Functional Rating Scale–Revised (ALSFRS-R) in the time-to-event analysis. Results Among the 1057 case participants and 5281 population control participants, the mean (SD) age at diagnosis of the case participants (ie, date of selection of the control participants) was 67.5 (11.5) years, and 3363 (53.1%) were male. In the population comparison, prescribed use of common psychiatric medications across all studied time windows before ALS diagnosis was associated with a higher risk of ALS (eg, among individuals prescribed hypnotics and sedatives 0-1 year before diagnosis: odds ratio [OR], 6.10; 95% CI, 3.77-9.88; prescribed anxiolytics 1-5 years before diagnosis: OR, 1.60; 95% CI, 1.15-2.23; prescribed antidepressants >5 years before diagnosis: OR, 1.21; 95% CI, 1.02-1.44). Excluding the year before diagnosis from the analysis, prescribed use of anxiolytics (OR, 1.34; 95% CI, 1.12-1.60), hypnotics and sedatives (OR, 1.21; 95% CI, 1.02-1.43), or antidepressants (OR, 1.26; 95% CI, 1.06-1.49) was associated with an increased risk of ALS. Similar results were noted in the comparison with relative control participants, partially alleviating the concern on familial confounding, with the exception of hypnotics and sedatives. Shorter survival was demonstrated among patients with ALS who had prediagnostic use of anxiolytics (hazard ratio [HR], 1.52; 95% CI, 1.12-2.05) or antidepressants (HR, 1.72; 95% CI, 1.30-2.29), compared with patients with ALS without such experience. Conclusions and Relevance In this case-control study, prescribed use of anxiolytics, hypnotics and sedatives, or antidepressants was associated with a higher subsequent risk of ALS. Prediagnostic use of such medications was also associated with a poor prognosis after ALS diagnosis.